title: Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells.
abstract: Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3-deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3-null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3-null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin-ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Moretti
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Michael
authors.initials: M
authors.lastname: Abadier
authors.forename: Raphael
authors.initials: R
authors.lastname: Ruppert
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology
chemical_list: D003598:Cytoskeletal Proteins; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D019010:Vascular Cell Adhesion Molecule-1; C527818:kindlin-3 protein, mouse
keywords: EAE; integrin affinity